| HUMORAL SPECIFIC IMMUNE RESPONSE
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| Humoral- or antibody-mediated specific immunity is directed at extracellular infection, especially by bacteria and their products, and also at the extracellular phase of viral infection and individual cell transplantation
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| Humorally mediated immune reactions require a soluble and cell-free antigen receptor to match the soluble and cell-free nature of the antigens. The act of antibody binding to antigen may go some way to counter the antigen's poten-tial for causing harm, by blocking the adhesion of bacteria or viruses, or the effect of bacterial toxins on the hosts cells - a process termed neutralization. However, simple binding, in most situations, will not guarantee elimination of the antigen. These two issues are dealt with by generating secreted forms of the B cell receptor - recognized as immunoglobulin - and giving it an additional effector function. This is provided by the nonantigen binding (Fc) part of the molecule and it is capable of recruiting components of the nonspecific immune response. The secreted immunoglobulins have effector functions encoded in the nonantigen-binding fragment of the molecule. This is achieved by genetic recombinations of the heavy chain genes, additional to those present to generate diversity and specificity of the antigen-binding component. Thus the original antigen specificity is preserved whilst effector functions can alter.
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| As with T cells, B cell subsets are operative in the humoral immune response
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| However, unlike the T cell subsets which are categorized on a functional basis, B cell subsets are defined by the timing of their participation in the humoral response. The B1 subset is responsible for the production of antibody that appears during the earliest stages of development of the organism. This subset and the antibodies it produces persist as a carryover from this period. Although these cells possess a lesser degree of specificity than the antibodies produced later by the more mature B2 cells, they form a relatively effective first line of defense against a broad spectrum of antigens. Similar to T cell subsets, it is possible to distinguish these subsets on the basis of their phenotypic properties: B1 cells express CD5 in addition to CD19 and CD20 found in the B2 population. It may be this population of B cells, that is responsible for the production of autoantibodies when dysregulated - this is but one of many theories of the pathogenesis of autoimmune reactions. As noted earlier, T cells, particularly Th cells interact with B cells both directly and indirectly via cytokines. This happens to such a degree that effective B cell responses are described as being T cell-dependent.
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| Antibodies illustrate the capability of the immune system for diversity
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| The normal human immune system is apparently capable of producing a limitless number of antibodies with the ability of recognizing any and all nonself elements it comes into contact with. Antibodies therefore represent an excellent demonstration of the diversity of the immune response with regard to its ability to recognize antigen and its methods for antigen elimination. The terms antibody, gamma globulin and immunoglobulin are synonymous.
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| Five classes of immunoglobulin are recognized: IgG, IgA, IgM, IgD, and IgE, with subclasses being recognized for IgG (IgG1, 2, 3, and 4) and for IgA (1 and 2). When studied at the individual molecular level, no other proteins show such amino acid sequence variation between individual members of the same class or subclass. This is most evident in the NH2-terminal domains of both heavy and light chains. As mentioned earlier, antibodies are capable of discriminating between the molecules that characterize the outer capsular coverings of differing bacterial species and may vary by a single amino acid or a monosaccharide residue. This is a consequence of the dimensions of the area recognized by the antibody molecule being 10 × 20 Å (10-10m) and thus being significantly influenced by the alteration in three-dimensional conformation brought about by the change of a single residue.
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| Antibodies are also good examples of how function is intimately related to structure. They are Y-shaped molecules. The arms interact with antigen and the stem provides additional or effector functionality. This secondary or effector function endows the antibody with an ability to not only recognize the antigen but also to help eliminate it.
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| The activation of the complement system (a component of nonspecific immune response, discussed above) is one of the most important antibody effector functions of the specific immune response
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| Figure 36.9 Complement activation pathways. There are three possible pathways of complement activation. Only the classical pathway is triggered by the specific immune response. The mannose binding ligand (MBL) pathway and the alternative activation pathway are triggered directly by microbes and their products. |
| This is achieved by using a set of components termed the 'classical activation pathways', which comprise C1q, C1r, C1s, C4, and C-2. Sequential activation of these components leads to the activation of the pivotal and critically important C-3 component, which is an absolute requirement for full complement activation. Once this is achieved, the terminal membrane attack complex, which comprises the components C5, C6, C7, C8, and C9, is activated. This complex eventually generates the polymeric ring structure that inserts into the
cell membrane of bacteria and is responsible for cell lysis. This classical pathway is triggered by C1q binding IgG or IgM that is already bound to its specific antigen (Fig. 36.9).
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| Two other pathways of activation exist, both constituting parts of the nonspecific immune response; they are probably older in evolutionary terms. These are the alternative pathway, which can be activated by lipopolysaccharide such as is found in Gram-negative bacterial walls, and the mannose binding ligand (MBL) pathway, which can be activated by mannose and other particular carbohydrates found in the cell wall of fungi, bacteria and viruses. The effector functions of antibodies are summarized in Table 36.2.
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